Download Screening for colorectal cancer

DR. Mojibina
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The availability and acceptability of early invasive
diagnostic methods (eg, chorionic villus sampling)
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The continued need for second trimester screening for
open fetal neural tube defects
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 Women
with singleton pregnancies
underwent: first-trimester combined
screening:
◦ measurement of nuchal translucency
◦ pregnancy-associated plasma protein A
[PAPP-A]
◦ The free beta subunit of human chorionic
gonadotropin (HCG) at 10 weeks 3 days
through 13 weeks 6 days of gestation
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 maternal
age was combined with fetal
NT
 and
maternal serum biochemistry (free
β-hCG and pregnancy-associated plasma
protein (PAPP-A))
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◦ measurement of:
 alpha-fetoprotein
 total human chorionic gonadotropin
 unconjugated estriol
 inhibin A at 15 through 18 weeks of
gestation
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This is a new technique
use of the phenomenon of fetal blood cells gaining
access to maternal circulation through the placental
villi
only a very small number of fetal cells enter the
maternal circulation in this fashion
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fetus has two major blood proteins:
albumin and alpha-fetoprotein (AFP)
Since adults typically have only albumin in their blood
the MSAFP test can be utilized to determine the levels
of AFP from the fetus
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 the
gestational age must be known with
certainty
 the amount of MSAFP increasses with
gestational age
 the MSAFP can be elevated for a variety of
reasons
 which are not related to fetal neural tube
or abdominal wall defects, so this test is not
100% specific
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a
neural tube defect in the fetus:
 from failure of part of the
embryologic neural tube to close
 there is a means for escape of more
AFP into the amniotic fluid
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Neural tube defects (NTD): second most
prevalent congenital anomaly in the United
States
Two factors have played a significant role in the
prevention of this disorder in developed
countries:
◦ Sonographic imaging combined with
amniocentesis for diagnosis of affected fetuses
◦ folic acid supplements for prevention of the
disorder
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The frequency of NTDs is increased with exposure to certain
environmental factors:
◦ drugs (valproic acid, carbamazepine, Folic acid deficiency)
◦ diabetes mellitus
◦ Obesity
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Adequate folate is critical for cell division due to its essential
role in the synthesis of:
◦ nucleic
◦ certain amino acids
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the observations that NTDs have a high rate:
◦ in monozygotic twins
◦ more frequent among first degree relatives
◦ more common in females than males
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The risk of recurrence for NTDs: approximately 2 to 4
percent when there is one affected sibling
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With two affected siblings, the risk is approximately: 10
percent
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The risk of NTD according to family history:
◦ to be higher in countries such as Ireland where the prevalence if
NTDs is high
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The genetic polymorphisms :
mutations in the methylene tetrahydrofolate reductase gene
may increase the risk for NTDs
Folate is a cofactor for this enzyme
which is part of the pathway of homocysteine metabolism in
cells
The C677T and the A1298C mutations are associated with
elevated maternal homocysteine concentrations and an
increased risk for NTDs in fetuses
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can be accomplished by supplementation of the
maternal diet with only 4 mg of folic acid per day
but this vitamin supplement must be taken a month
before conception and through the first trimester
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This test is most commonly used as a test for
pregnancy
Later in pregnancy: in the middle to late second
trimester
the beta-HCG can be used in conjunction with the
MSAFP to screen for chromosomal abnormalities,
and Down syndrome in particular
An elevated beta-HCG coupled with a decreased
MSAFP suggests Down syndrome
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 made
by the fetal adrenal glands
 Estriol
tends to be lower when Down
syndrome is present
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 An
increased level of inhibin-A is
associated with an increased risk for
trisomy 21
A
high inhibin-A may be associated with
a risk for preterm delivery
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BRCA1 AND BRCA2 GENES
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Breast cancer develops in about12 percent of women who
live to age 90
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a positive family history is reported by 15 to 20 percent of
women with breast cancer
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Just only 5 to 6 percent of all breast cancers are associated
with an inherited gene mutation
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 Two
major susceptibility genes for
breast cancer, BRCA1 and BRCA2
 Testing
for mutations in these genes, is
available
 Clinicians
and patients must decide
when it is appropriate to screen for
their presence
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As an essential part of the normal mechanisms that repair
double-strand DNA breaks (ionizing radiation and DNA cross
linking agents such as cisplatin)
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through recombination with undamaged, homologous DNA
strands
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 Cisplatin
is a platinum-based chemotherapy
drug
 used
to treat various types of cancers, such as
sarcomas, some carcinomas, lymphomas and
germ cell tumors
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works by crosslinking across DNA inter-strands
making it impossible for rapidly dividing cells to
duplicate their DNA for cell division (mitosis)
The damaged DNA sets off DNA repair mechanisms
which fails to work
so in turn activate cell death processes (apoptosis)
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The reason why BRCA mutations predispose mainly to
breast and ovarian cancers is unclear
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intact BRCA1 represents a barrier to transcriptional
activation of the estrogen receptor
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that functional inactivation could lead to altered
hormonal regulation of mammary and ovarian
epithelial proliferation
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Cancer risk with a high penetrance
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women who have inherited mutations
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the lifetime risk of breast cancer is between 65 and 85
percent by age 70
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Ovarian cancer is also linked to the presence of BRCA
mutations
the lifetime risk of ovarian cancer:
◦ between 45 and 50 percent in women who have a deleterious
BRCA1 mutation
◦ and 15 to 25 percent for those with a BRCA2 mutation
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prostate cancer
male breast cancer
pancreatic cancer
Although the risk of male breast cancer and pancreatic
cancer may be under 10 percent
the risk of prostate cancer in BRCA2 carriers may be as
high as 35 to 40 percent
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 The
gene Locus for BRCA1: 17q21
 a large gene
 24 exons
 encoding a 220 kD
 1863 amino acids
 Two recognizable motifs
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 BRCA2
(13q12.3)
 was identified by Wooster et al. in 1995
 It encodes for 384 kD nuclear protein
 3418 amino acids
 BRCA2 bears no homology to any known
tumour supressor genes
 contains 27 exons
 spread over 70 kb of genomic DNA
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Degree of relatedness to affected relatives
Number of affected relatives
The age of the relative(s) when breast cancer occurred
Laterality of the disease in affected relatives
Whether there is a family history of ovarian cancer
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Screening for colorectal cancer
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Colorectal cancer (CRC) is
◦ a common
◦ Lethal
◦ preventable disease
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It is infrequent before age 40
the incidence rises progressively to 3.7/1000 per year
by age 80
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Before deciding how to screen:
clinicians should decide whether the individual patient is at
average or increased risk
based on his or her medical and family history
A few simple questions are all that is necessary:
Have you ever had colorectal cancer
or an adenomatous polyp
Have you had inflammatory bowel disease (Crohn disease)
Has a family member had colorectal cancer or an adenomatous
polyp
If so, how many
was it a first-degree relative (parent, sibling, or child)
and at what age was the cancer or polyp first diagnosed
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 an
inflammatory bowel disease
 causes inflammation of the
gastrointestinal tract in both men
and women
 persistent diarrhea, abdominal pain,
fever, and at times rectal bleeding
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 Patients
at highest risk with familial
syndromes (HNPCC, FAP)
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be screened for CRC with
colonoscopy at frequent specified
intervals
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a first-degree relative with colon cancer
or adenomatous polyp diagnosed at age <60 years
or two first-degree relatives diagnosed at any age
should be advised to have screening colonoscopy
starting at age 40 years
or 10 years younger than the earliest diagnosis in
their family
whichever comes first, and repeated every five years
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•Hereditary
nonpolyposis colorectal cancer
(HNPCC)
•the most common of the well-defined
colorectal cancer syndromes
•accounting for at least 2% of the total colorectal
cancer
•carrying a greater than 80% lifetime risk of
cancer
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 can
be detected in approximately 90% of
tumors from individuals with Hereditary
Non-Polyposis Colorectal Cancer (HNPCC)
 MSI is also reported in approximately
15% of sporadic colorectal carcinomas
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responsible for the MSI of the HNPCC tumors
In contrast to the classical tumor suppressor pathway
the mismatch-repair gene tumor pathway accumulates
mutations in genes involved in tumorigenesis
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 can
be accomplished by appropriate
clinical cancer screening of HNPCC
patients with mutations in mismatch
repair (MMR) genes
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In individuals with cancer
mutation detection can be accomplished relatively
efficiently by germline mutation analysis of individuals
(blood) whose cancers show microsatellite instability
(MSI)
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Among 378 adenoma patients
six (1.6%) had at least one MSI adenoma
Five out of the six patients (83%) had a germline MMR gene
mutation
MSI analysis is a useful method of prescreening colorectal
adenoma patients for HNPCC
Microsatellite Instability in Adenomas as a Marker for Hereditary Nonpolyposis
Colorectal Cancer
Anu Loukola et al. American Journal of Pathology. 1999;155:1849-1853
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Cells deficient for both alleles of a mismatch repair gene,
leading to somatic mutations
which can be demonstrated by analyzing microsatellite
sequences in the tumor DNA
These sequences display frequent somatic deletions and
insertions, often referred to as microsatellite instability (MSI).
HNPCC patients form adenomas at a slightly but not strikingly
increased rate as compared with the general population
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The frequency of the MSI is 80 to 95% in HNPCC
cancers
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10 to 15% in sporadic colorectal cancers
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The presence of the factor V mutation can cause an
increased risk of venous thrombosis
Individuals heterozygous for the Factor V Leiden (FacV)
mutation :
◦ carry an eight-fold greater risk for thrombosis
◦ while homozygosity confers an estimated ninety-fold
increased risk
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The most extensively studied biomarker of
inflammation in cardiovascular diseases
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serum C-reactive protein (CRP)
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Elevated serum CRP was a strong independent risk
factor for cardiovascular disease
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added to the predictive value of other factors, such as
serum total cholesterol
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Elevated serum CRP was a stronger predictor of
cardiovascular events than LDL cholesterol (LDL-C) At
eight years
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Although mortality from coronary heart disease (CHD)
has fallen substantially over the past three decades
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it remains the leading cause of death in adults
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risk factors for CHD, including:
◦ Hypertension
◦ Hypercholesterolemia
◦ Smoking
◦ a family history of premature CHD
◦ and diabetes mellitus
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The Association Between
Apolipoprotein E
Polymorphism and Cardiovascular
Risk Factors
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 the
allelic and genotypic frequencies
related to apolipoprotein E (ApoE)
polymorphism
 association of the genotypes with risk
factors
 and cardiovascular morbidity in
population
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the gene amplification technique through the
polymerase chain reaction-restriction fragment length
polymorphism
(PCR-RFLP) and cleavage with the restriction
enzyme Hha I to identify the ApoE genotypes The most
frequent
Individuals with the E3E4 had a mean age greater than
those with the E3E3
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Cystic fibrosis: Prenatal genetic
screening
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Cystic fibrosis (CF) is a chronic pulmonary
and exocrine pancreatic disease
the most common monogenic disorder in
Caucasians of Northern European
classic form it is marked by abnormal sweat
chloride levels
chronic pulmonary disease
pancreatic insufficiency
liver disease
and obstructive azoospermia in males
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an autosomal recessive disease
with a carrier rate of 1 in 22 to 25 in Caucasian
Americans of Northern European background
the most common mutation in this group is called F508
and accounts for 75 percent of all CF cases
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The key to all CF screening is knowing which mutations
to test for
knowledge of the most common CF mutations in
individuals of different heritages
Native Americans are at increased risk of CF (carrier
frequency 1 in 31
Jewish heritage (carrier rates ranging from 1 in 24 to 1
in 29 if the patient's ancestors originated in Greece,
Bulgaria, or Libya)
to 1 in 90 if the ancestors originated in Iran or Iraq)
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The diagnosis and treatment is complicated:
not everyone who is homozygous for the CF mutation has
the classic form of the disease
Some individuals have an atypical presentation:
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have only isolated features of the disease:
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◦ pulmonary disease associated with pancreatic
sufficiency
◦ pancreatitis
◦ liver disease
◦ nasal polyps
◦ congenital bilateral absence of the vas deferens
(CBAVD)
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hemoglobinopathies as two general types:
◦ the thalassemias
◦ decreased globin chain production
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hemoglobin variants (eg, sickle cell anemia and its variants,
hemoglobin C disease)
chronic, debilitating, and often fatal
new therapies:
◦ including hydroxyurea (XMNI, g mRNA>active)
◦ hematopoietic cell transplantation
◦ gene therapy
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Family history of a relative with a hemoglobinopathy or
thalassemia
 couples from extended families living in endemic areas
 consanguineous marriages are common, may be at
highest risk
 Ethnic background:
◦ at low risk for hemoglobinopathies are
northern Europeans
◦ Japanese
◦ Native Americans
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mean corpuscular volume (MCV) <80 femtoliters (fL), MCH<
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in the absence of iron deficiency (alpha or beta thalassemia)
Hemoglobin electrophoresis:
this test will identify carriers:
◦ hemoglobin variants
◦ beta thalassemia
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